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A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and

Cécile Lemaître1,2,3, Jhen Tsang1,2, Caroline Bireau1,2

  • 1CNRS, UMR 9196, Institut Gustave Roussy, Villejuif, France.

Plos Pathogens
|June 27, 2017
PubMed

Insights

Human endogenous retroviruses (HERVs), specifically HERV-K(HML2) Env protein, can promote cancer progression. This protein induces epithelial-mesenchymal transition and activates signaling pathways linked to cell transformation and metastasis.

Area of Science:

  • Genomics
  • Molecular Biology
  • Oncology

Background:

  • Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections integrated into the host genome, comprising about 8% of human DNA.
  • While most ERVs are silenced, some, like the HERV-K(HML2) family, remain transcriptionally active and can produce viral particles and proteins.
  • HERV-K(HML2) is notably amplified and retains full-length coding genes, with its proteins detected in various cancers, including melanoma and breast cancer.

Purpose of the Study:

  • To investigate the oncogenic potential of the HERV-K(HML2) envelope (Env) protein.
  • To determine the molecular mechanisms by which HERV-K(HML2) Env influences cellular behavior related to cancer.
  • To explore the role of HERV-K(HML2) Env in inducing cellular transformation and metastasis.

Main Methods:

  • Expression of HERV-K(HML2) Env in a non-tumourigenic human breast epithelial cell line.
  • Analysis of epithelial-mesenchymal transition (EMT) markers, cell morphology, and motility.
  • Microarray analysis in 293T cells to identify induced transcription factors.
  • Western blotting and pathway analysis to assess MAPK ERK1/2 activation.
  • Comparative analysis with other retroviral Env proteins.

Main Results:

  • HERV-K(HML2) Env expression induced EMT, characterized by altered molecular markers, cell morphology, and increased motility in breast epithelial cells.
  • Microarrays identified ETV4, ETV5, and EGR1 as key transcription factors upregulated by HERV-K(HML2) Env.
  • HERV-K(HML2) Env activated the MAPK ERK1/2 pathway, dependent on its cytoplasmic tail.
  • This transforming activity was specific to HERV-K(HML2) Env and Jaagsiekte Sheep Retrovirus (JSRV) Env.

Conclusions:

  • The HERV-K(HML2) Env protein possesses oncogenic properties that can contribute to cancer aggressiveness and metastasis.
  • Activation of the MAPK ERK1/2 pathway and induction of specific transcription factors are key mechanisms underlying Env's effects.
  • HERV-K(HML2) Env represents a novel factor potentially involved in oncogenesis, particularly in cancers where it is expressed.

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